Hematopoietic growth factors, such as erythropoietin (EPO) and interleukin- 3 (IL-3) activate specific cytokine receptors on the surface of immature blood cells, thereby leading to cellular proliferation and differentiation. Defects in cytokine receptor signaling can lead to ineffective hematopoiesis deficiency; constitutive activation of receptor signaling can lead to overproliferation and leukemogenesis. One pathway activated by cytokine receptors, the JAK/STAT pathway, accounts at least in part for the specificity of the signal transmitted by each cytokine. Using an interactive strategy of mammalian cell culture, transgenic mouse technology, and Drosophila genetics, we plan to study various aspects of the JAK/STAT pathway. In Specific Aim #1, having identified a point mutation (a hyperactive mutation) in a Drosophila JAK kinase that causes "fly leukemia", we will explore the effects of overexpressing a hyperactive jAK2 kinase cells or transgenic mice. In Specific Aim #2, having identified a mutant form of a Drosophila STAT protein that suppresses "fly leukemia", we will construct and assay dominant inhibitory forms of mammalian STAT proteins. In Specific Aims #3 and #4 we will explore the interaction of the JAK/STAT path signaling pathway with other signaling pathways, such as the Ras/Raf/MAP kinase pathway. Finally, in Specific Aim #5, we will characterize a novel signaling pathway that is specifically activated by the betac subunit of the IL-3 Receptor and evaluate its relationship to the JAK/STAT pathway.